It has been a few weeks since the 2012 annual meeting of the American Society of Hematology (ASH) came to a close.

A substantial amount of research regarding myelodysplastic syndromes (MDS) was presented at the meeting, some of which has been summarized in our daily updates about the meeting.

This article focuses on the bigger picture: What were the key findings of the meeting? Were there results with immediate implica­tions for the treatment of MDS? Did the research at the meeting represent a major step forward for MDS patients, or was it more incremental in nature?

To address these questions, the Beacon Staff consulted with several top MDS specialists to get their assessment of the MDS-related research presented at the meeting.

This article summarizes feedback The Beacon received from Dr. David Steensma from the Dana-Farber Cancer Center in Boston, Dr. Azra Raza from Columbia University, Dr. Ruben Mesa and Dr. Raoul Tibes from the Mayo Clinic in Arizona, Dr. Bart Scott from the Seattle Cancer Care Alliance, and Dr. Mikkael Sekeres from the Cleveland Clinic.

The Bottom Line: Small Steps Toward Better Understanding The Biology Of MDS, But Not Many New Treatments For MDS

Overall, there was some good news for MDS patients and caregivers coming out of the 2012 ASH meeting. But the amount of good news was limited, and there certainly was no research presented at the meeting news that can be classified as “great” or “earth-shattering.”

As Dr. Raza explained, “Among the key clinical research presented at this year’s ASH meeting, there were three areas of interest: how to use old drugs better, how to predict response, and new targets and clinical trials of interest.”

Dr. Steensma further explained, “The ASH Annual Meeting this year included a number of important studies about the biology of MDS, especially the importance of specific gene mutations, but was lean with respect to new therapies.”

Several new proteins were identified that can help physicians predict which patients are likely to respond to Vidaza (azacitidine), Revlimid (lenalidomide), or stem cell transplantation.

In addition, two studies investigated ways of modifying or adding to currently available treatment options for MDS, with the hope of improving them. Both were early-stage studies, though, that did not directly compare the alternative treatment approaches with the current methods of using the drugs.

Still, in the longer term, these learnings may lead to additional treatment options for MDS patients.

In the meantime, the range of available MDS treatment options remains limited.

There was some encouraging research at the ASH meeting about two potential new MDS treatments – SGI-110 and Estybon (rigosertib, ON 01910.Na). However, in both cases, the research was from early-stage clinical studies, and there was no convincing evidence that either of these drugs will be real game changers. Furthermore, these drugs are several years away from being readily available to most MDS patients.

Advances In Currently Available MDS Treatments

Oral Azacitidine (Vidaza)

One study in particular was mentioned most often as a highlight of the meeting: a Phase 1 study showing that extended dosing of oral Vidaza (azacitidine) is effective and safe in lower-risk MDS patients (see related Beacon news).

“Overall response rates ranged from 39 percent for 14-day dosing to 30 percent for 21-day dosing. Among patients who were dependent on red blood cell transfusions at the start of the study, 47 percent and 33 percent of the patients in the two dosing groups, respectively, achieved transfusion independence,” said Dr. Raza.

“Based on these data, oral Vidaza administered once-daily in extended dosing schedules is active and well-tolerated and warrants further investigation,” she further stated.

Zolinza Plus Cytarabine

“After failure of Vidaza or Dacogen, treatment options for MDS patients are limited if they do not proceed to/or are ineligible for allogeneic [donor] stem cell transplantation,” wrote Drs. Mesa and Tibes.

They therefore said that the meeting highlights included a Phase 1/2 study of Zolinza (vorinostat) plus low-dose cytarabine (Cytosar-U) in MDS patients for whom Vidaza treatment had previously failed. Overall, 17 percent of these patients responded to the Zolinza-cytarabine treatment.

Cytarabine is chemically related to both Vidaza and Dacogen (decitabine), two drugs approved in the United States and elsewhere for the treatment of MDS. Cytarabine also is approved in some countries as a treatment for MDS, although it is not approved by the U.S. Food and Drug Administration for that use.

New Agents Being Tested For MDS

Research results related to several potential new drugs being studied for the treatment of MDS were mentioned as among the highlights of this year’s ASH meeting.

SGI-110

SGI-110, which is being developed by Astex Pharmaceuticals (NASDAQ: ASTX), is an inactive version of Dacogen that gets converted to Dacogen by the body. It is designed to stay in the body longer than Dacogen and to be able to be given by subcutaneous injection.

Results from a Phase 1/2 study presented at the meeting showed that heavily pretreated MDS patients had clinical responses to SGI-110 and tolerated the treatment.

Estybon (Rigosertib)

Results from another Phase 1/2 study presented at this year’s meeting showed that a third of the heavily pretreated MDS patients included in the study responded to treatment with Estybon (rigosertib, ON 01910.Na).

Estybon is being developed by the biopharmaceutical company Onconova Therapeutics as a potential new treatment for MDS. Estybon works by selectively killing cancer cells and immature stem cells called blasts.

Advances In Supportive Care

Nplate

Updated results presented at ASH helped to assuage fears that Nplate (romiplostim), which increases the body’s production of platelets, significantly increases the risk of MDS progressing to acute myeloid leukemia (AML).

“We learned that the platelet growth factor romiplostim [Nplate] may be a little safer than we thought,” said Dr. Sekeres. “A Data Safety Monitoring Committee had stopped an ongoing study of the drug last year due to excess leukemia cases in the treatment arm compared to placebo arm; it now appears that may have been premature,” he explained.

Results presented at the ASH meeting showed that 6 percent of patients receiving Nplate and 5 percent of patients receiving a placebo progressed to AML during the 58-week follow-up period. The survival rates for that timeframe were 82 percent for the Nplate group and 80 percent for the placebo group.

Exjade

Final results from a study of Exjade (deferasirox) in transfusion-dependent MDS patients were also presented at the meeting. Exjade is a type of iron chelation therapy. Such therapies are used to remove excess iron that accumulates in the blood due to extended use of blood transfusions.

The results showed that 6 percent of patients achieved transfusion independence after 6 months of treatment with Exjade, 16 percent after 9 months, and 20 percent after 12 months.

Predicting Response Via A New Scoring System

Dr. Raza explained that the International Prognostic Scoring System (IPSS) was developed in 1997 as a way of predicting an MDS patient’s prognosis based on their chromosomal abnormalities, percent immature stem cells (blasts), and number of low blood cell counts. However, it only accurately predicts the prognosis of 39 percent of patients.

Therefore, a revised prognostic scoring system (IPSS-R) was developed this year. It uses the same parameters, but includes five rather than three categories of chromosomal abnormalities, and new cutoff values for blasts and blood cell counts.

“It is an improvement on the IPSS, but both systems are based on patients who have not been treated with disease-modifying drugs,” said Dr. Raza.

“It is no surprise that a number of groups presented research at ASH validating the system in their own patient cohorts, and on the whole it appears to be standing up fairly well,” said Dr. Sekeres.

The MDS experts identified two important studies presented at ASH that examined the usefulness of the IPSS-R.

The first study showed that the IPSS-R has strong prognostic value for survival in higher-risk MDS patients treated with Vidaza.

“This is the first study to show that the IPSS-R can be used with confidence in patients receiving this disease-modifying therapy,” said Dr. Sekeres.

Another study evaluated the IPSS-R for its ability to predict survival of MDS patients with a missing chromosome. The results showed that patients with a missing chromosome have very poor outcomes.

Predicting Response Via Biomarkers

Several presentations during this year’s ASH meeting sought to determine biomarkers that can be used to predict response to certain MDS treatments.

“Overall, approximately 25 percent to 50 percent of MDS patients achieve a complete or very good, clinically meaningful response to Vidaza, and often, responses are seen only after three to six months,” explained Drs. Mesa and Tibes. “Identifying those patients at the start of therapy who are at higher likelihood to respond would be of great clinical importance,” they added.

BH3 Profiling

Drs. Mesa and Tibes also explained that BH3 profiling is a test that can measure cell death after treatment.

One abstract presented at this year’s meeting showed that measuring the activity of BH3 proteins can predict sensitivity to Vidaza in a preclinical model.

“Based on these results, we are testing primary samples from patients treated with Vidaza to develop a predictive biomarker/assay for response to Vidaza in MDS and AML patients,” said Drs. Mesa and Tibes.

BCL2L10

Another study, which was conducted by French researchers, showed that the protein BCL2L10 is associated with resistance to Vidaza in MDS and AML.

According to Drs. Mesa and Tibes, the results showed that among MDS and AML patients treated with Vidaza, patients with higher percentages of BCL2L10-positive cells in bone marrow samples were more likely to have disease resistant to Vidaza and were more likely to have shorter survival.

RPS14 In MDS Patients Without Deletion In Chromosome 5

The presence of the chromosomal abnormality del(5q) is predictive of a good response to Revlimid (lenalidomide) in lower-risk MDS.

Dr. Raza cited a study from China that found that levels of the protein RPS14 may do the same for patients without del(5q).

The results showed that low levels of RPS14 are common in MDS patients without del(5q), and low levels of RPS14 were associated with prolonged survival and possible response to Revlimid in lower-risk MDS patients.

Common Mutations

Dr. Steensma referenced a study that found that currently known mutations do not strongly predict response to Vidaza or Dacogen. However, the study also showed that patients with mutations in either the TP53 or DNMT3A gene do very poorly with stem cell transplantation.

“New approaches are needed for that subset of patients,” said Dr. Steensma.

Biology Of MDS

According to the experts, the meeting included important presentations about the biology of MDS, especially the importance of specific gene mutations.

“New mutations are being identified which may lead to a better understanding of why patients get this disease and lead to new treatments,” said Dr. Scott.

Mutations in SETBP1

Researchers from the Cleveland Clinic, for example, newly identified a mutation in the gene called SETBP1 that may be associated with disease progression. The mutation was present in 5 percent to 15 percent of patients with MDS, chronic myelomonocytic leukemia, or secondary AML.

The mutation was associated with higher age, chromosome 7 abnormalities, shorter survival, and importantly, with evolution from MDS to AML.

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All of The Beacon’s coverage related to the ASH 2012 meeting can be found here. The coverage will continue in the New Year with additional in-depth articles about research presented at the meeting.